This Center for Biomedical Research Excellence (COBRE) will examine the neural mechanisms of schizophrenia by integrating multiple neuroimaging methods with psychiatric and neuropsychological testing, and incorporating genetic testing. Its overarching theme is the study of schizophrenia as a disorder characterized by abnormalities in structural, functional, and effective connectivity between cortical and subcortical brain regions producing abnormalities in the integration of information across distributed brain circuits. The program is composed of four tightly integrated projects conceptualized as a hierarchy in which each independently investigates a major cognitive domain of dysfunction in schizophrenia, as identified by a panel of experts in a recent NIH-sponsored study. This dysfunction ranges from basic sensory to higher-order deficits, with attention, memory, concept formation and problem solving abilities (i.e., intelligence) listed among the top cognitive deficits that detrimentally effected patients with schizophrenia. The plan begins at a basic level of sensory processing (auditory sensory gating;Project 1), followed by multi-sensory integration (auditory and visual;Project 2), to working memory and relational memory integration (transverse patterning;Project 3), and, finally, generalized higher cognitive functioning (intelligence;Project 4). Plans provide for data collection on up to 100 of the same patients with schizophrenia (schizophrenia) and 100 healthy normal volunteers (HNV) and a centralized data processing stream that has been implemented and is already in use. Project 1 quantifies brain function and clinical pathology through multimodal imaging of sensory gating. Project 2 studies the neural mechanisms underlying auditory and visual integration in schizophrenia and HNV using magnetoencephalography (MEG), electroencephalography (EEG) combined with anatomical magnetic resonance imaging (MRI), and functional MRI (fMRI). Project 3 tests the fronto-temporal disconnection hypothesis in schizophrenia by addressing basic clinical and translational research questions. Project 4 addresses whether general cognitive functioning in schizophrenia is related to particular white matter, metabolic, and volumetric changes in subcortical gray- and white-matter regions suggestive of frontosubcortical disconnection. These projects will produce a wealth of information about the nature of antomic and functional misconnections in schizophrenia and how they relate to the manifestation of the illness. Overall, the committee recommended this outstanding application for five years of support with the budget as requested.